Treatment in Vitamin D-Dependent

and Vitamin D-Resistant


Francis H. Glorieux Use of 1,25(OH),D, (calcitriol) can be of benefit in the treatment of two hereditary types of rickets and osteomalacia, vitamin D dependency type I (VDDl ) and X-linked hypophosphatemic vitamin D-resistant rickets (HPDR). VDDl is due to inadequate activation of 25(OH)D to 1,25(OH),D, leading to very low circulating levels of 1,25(OH),D in plasma; the basic abnormality appears to be an alteration in renal la-hydroxylase activity. In VDDl, replacement therapy with calcitriol results in complete correction of the abnormal phenotype. By contrast, in HPDR, plasma levels of 25(OH)D and 1,25(OH),D are in the normal range, although it has been demonstrated that the ability of patients to produce 1,25(OH),D under conditions of stress is impaired. When started early in life, the use of phosphate salts in HPDR generally results in healing of rickets, normal growth, and correction of lower limb deformities. However, osteomalacia is not corrected by treatment with phosphate, either alone or in combination with vitamin D. By pharmacologically increasing the level of 1,25(OH),D, in these patients, there is often a dramatic improvement in the appearance of the trabecular surface, leading to correction of the osteomalacic component of HPDR; in addition, the secondary hyperparathyroidism observed in previous patients treated with phosphate and vitamin D is easier to control. Closed medical follow-up allows the prevention of renal damage that could result from long-term administration of calcitriol. @ 1990 by W.B. Saunders Company.


LTHOUGH DIETARY INTAKE of vitamin D has, for many years, been generally adequate throughout North America, especially since the advent of vitamin D-fortified milk, rickets and osteomalacia continue to be encountered in both the United States and Canada. A wide range of metabolic disorders, some hereditary and others acquired, account for the persistence of these conditions; consequently a variety of therapeutic approaches exist. This brief report focuses on two hereditary types of rickets and osteomalacia for which treatment with 1,25(OH),D, (calcitriol) has proven to be of considerable benefit: pseudo-vitamin D deficiency or vitamin D dependency type I (VDDl), and X-linked hypophosphatemic vitamin D-resistant rickets (HPDR). CLASSIFICATION

While both rickets and osteomalacia involve defective mineralization of the organic matrix of the skeleton, they are anatomically distinct. In rickets, the pathologic changes involve the epiphyseal growth plate, whereas in osteomalacia the decrease in calcification rate is most evident along the trabeculae, leading to excessive accumulation of osteoid tissue. In general, one thinks of rickets in terms of the growing skeleton and of osteomalacia in terms of the adult skeleton. The various forms of rickets and osteomalacia may generally be classified as resulting from a decreased availability of either calcium or phosphate. VDDl belongs to the first group, while HPDR is the epitome of the hypophosphatemic variety.

From the Genetics Unit, Shriners Hospital, and the Departments of Surgery, Pediatrics, and Human Generics. McGill University, Montrgal, Qubbec, Canada. Address reprint requests to Francis H. Glorieux, MD, PhD, Genetics Unit, Shriners Hospital, 1529 Cedar Ave, Mont&al, Qutbec. Canada, H3G lA6. @ 1990 by W.B. Saunders Company. 00260495/90/3904-1008$3.00/O





VDDl patients present with progressively decreasing serum calcium levels, and first normal then depressed serum phosphate levels. The term vitamin D dependency is used because these patients generally respond to pharmacologic doses of vitamin D.’ The disease is characterized by low plasma concentration of 1,25(OH),D.* In contrast, vitamin D dependency type 2 (VDD2) is characterized by elevated levels of 1,25(OH),D and results from end-organ resistance to 1,25(OH)2D.3 Though infrequent in the United States, VDDl has been identified in a number of families in Quebec. Based on pedigree and linkage studies, we have recently mapped the VDDl gene to the long arm of chromosome 12 on the segment q14 between the COL2Al (type II procollagen) gene and a haplotype made of three closely linked DNA probes.4 The basic abnormality in VDDl appears to be an altered activity of the renal la-hydroxylase enzyme that activates hydroxylation of 25(OH)D into 1,25(OH),D; the exact nature of the mutation is not known. It is also uncertain whether the remaining circulating levels of 1,25(OH),D may derive from an extrarenal source. The latter possibility is suggested by the finding of a total absence of renal lahydroxylase in a piglet model for the disease.’ In addition, our group has recently demonstrated that human decidual cells, which can produce 1,25(OH),D under normal conditions, do not produce any 1,25(OH),D when the cells are harvested from the placenta of VDDl subjects (unpublished results). Although patients with VDDl respond well to the daily administration of large oral doses of vitamin D, the long-term monitoring of such a treatment is not easy. Indeed, the therapeutic doses (25 to 75,000 IU/d) are close to the toxic doses and place the patient at risk for nephrocalcinosis and impaired renal function. Furthermore, because of the tissue accumulation of vitamin D, rapid adjustment in case of overdose is not possible. Given these drawbacks and the fact that patients with VDDl have insufficient production of


No 4, Suppl 1 (April), 1990: pp lo-12



1,25(OH),D, it appears logical that treatment of choice is replacement therapy with physiologic amounts of calcitriol. Such therapy results in complete correction of the abnormal phenotype, eliminating both the hypocalcemia and radiographic evidence of the disease.6 If treatment is started shortly after birth, it will probably also prevent the severe hypoplasia of tooth enamel that is a common complication of this form of rickets. The regimen of calcitriol that we use calls for an initial dose of 2 to 3 fig/d, continued until the bone disease is healed (usually about 2 to 5 months) and followed by a low (physiologic) maintenance dose of 0.25 to 1 pg/d to be continued throughout life. In two of our patients who became pregnant, we not only continued calcitriol administration, but increased it (by 50% to 100% of the maintenance dose) because levels of 1,25(OH),D normally increase during pregnancy; both women gave birth to normal children. In order to assess the potential nephrotoxic effects of calcitriol, we observed a group of patients with VDDl for a mean of 8.1 years. The patients were monitored in terms of urine and serum calcium, echogenicity of the renal pyramids (ERP), creatinine clearance, and slit-lamp examination of the cornea looking for calcium deposits. As expected, hypercalciuria was common, since we used it as an index for adjusting the daily dose. Hypercalcemia occurred less frequently, but ultrasonography frequently showed an image of density that has been related to nephrocalcinosis7; however, the image has not changed over time. Two patients have shown a decrease in creatinine clearance (2.5 SD below the normal mean for age). Slit-lamp examination revealed calcium deposits in the cornea of both subjects (minimal in one case and clear in the other), as well as in a third patient; all three patients had a past history of vitamin D intoxication. Thus, while cornea! examination appears to be a good index to follow on a long-term basis, calcium deposits seem to reflect a past history of difficulty with vitamin D more than they do the effects of therapy with calcitriol.* X-LINKED





While HPDR is associated with pronounced skeletal deformities, patients are otherwise healthy. Clinically, the hallmarks of this X-linked dominant trait, are shortness of stature, bowed legs, and hypophosphatemia due to a parathyroid hormone (PTH)-independent decrease in renal phosphate reabsorption.’ Read et al have mapped the gene on the short arm of the human X chromosome.” Work is proceeding in several laboratories to locate closer gene markers in an effort to isolate the abnormal gene product. The biochemistry of HPDR is characterized normocalcemia, hypophosphatemia, and renal phosphate wastage evidenced by a decreased maximal tubular reabsorbtion of phosphate, per volume of glumelur filtrate (TmP/GFR; an assessment of the maximum rate of tubular phosphate reabsorption).” Children with this disease do not develop hyperparathyroidism in the untreated state and do not exhibit vitamin D deficiency. Levels of ZS(OH)D and 1,25(OH),D in plasma are in the normal range.” While the

amount of 1,25(OH),D is sufficient to allow for normal calcium homeostasis, it has been demonstrated that the ability of patients with HPDR to produce calcitriol under conditions of stress is impaired,13 probably due to abnormal fluxes of phosphate through the renal proximal tubular cell. Drezner has shown a positive correlation between renal TmP/GFR and plasma 1,25(OH),D levels in normal adults and in a group of patients with HPDR, tumor-induced osteomalacia, and tumoral calcinosis, suggesting a relationship between renal phosphate transport and the prevailing 1,25(OH),D plasma levelsI However, we did not find such a correlation, either in a group of normal children or in children with untreated HPDR. This discrepancy may be related to the loosely controlled synthesis of 1,25(OH),D in childrenI Given that phosphate loss is the central problem in HPDR, oral phosphate supplements have been the key to therapy for this condition. When started early in life, daily administration of phosphate salts, in divided doses, generally results in healing of rickets, normal growth rate, and correction of lower limb deformitiesI However, when we looked at the osteomalacic component of the disease, we found that thick osteoid seams and decreased mineral apposition rate along the trabeculae were not corrected by treatment with phosphate, either alone or in combination with large amounts of vitamin D. Thus, there appears to be a discrepancy between the response at the growth plate and the response at the trabecular surface.” To try to correct the latter problem, we decided to shift from giving vitamin D to giving calcitriol in an effort to increase the plasma levels of 1,25(OH),D,. This approach was based on our observation that serum 1,25(OH),D levels in children with HPDR were lower in those receiving phosphate supplements than in those in the untreated state.12 By pharmacologically increasing the level of 1,25(OH),D,, we have been able to document, albeit not in all cases, a dramatic change in the appearance of the trabecular surface associated with healing of osteomalacia.” Similar results have been reported by others.‘9-22To the extent that such an approach is not uniformly effective, and based on the specific presence of hypomineralized periosteocytic lesions,23 we have proposed that the osteoblast may be another important target for the HPDR mutation.24 Nonetheless, our current approach is to give 0.75 gg to I .O pg of calcitriol daily in two divided doses. The phosphate salts are administered five times over the 24-hour period. The dosage of phosphate is monitored by doing a titration curve once a year. After withdrawing phosphate supplements for 12 hours while maintaining regular calcitriol intake, we measure serum phosphate before, and 45 to 60 minutes after the morning phosphate dose; the optimal single dose is that which produces an increase in serum phosphate of approximately 1.5 mg/dL. This dose is then multiplied by five to obtain the total daily dosage.‘* Calcitriol dosage is monitored by measuring urinary calcium every 3 months on random morning samples; urinary calcium (mg)/creatinine (mg) must be less than 0.3.



In addition, parathyroid hormone levels are measured at 6-month intervals because of the tendency for phosphate therapy to trigger a secondary hyperparathyroidism that may be difficult to control. I6 Adjustment of the phosphate dosage is made accordingly. Since we shifted to calcitriol, the severe hyperparathyroidism observed in our earlier patients on phosphate and vitamin D has not been observed. This may be linked to the effect of oral calcitriol in inhibiting the secretion of parathyroid hormone, and possibly to the effect of the metabolite on intestinal calcium absorption. Whatever the case, it is our experience that iatrogenic hyperparathyroidism is now easier to control with calcitriol. We have also evaluated the possible nephrotoxicity of the metabolite in over 20 patients under long-term therapy. Current data

indicate that despite frequent episodes of hypercalciuria and high incidence of increased ERP, renal function is not altered.* CONCLUSION

Although we do not fully understand the mutation underlying VDDl at the molecular level, it is clear that the disease can be completely controlled on a long-term basis by treatment with calcitriol. With regard to HPDR, we have found that pharmacologic use of calcitriol in conjunction with phosphate therapy can dramatically improve the lives of these patients. In both instances, the benefits of calcitriol therapy vastly outweigh the potential risks of iatrogenic renal damage, provided that close medical follow-up is maintained.


1. &river CR: Vitamin D dependency. Pediatrics 45361-363, 1970 2. Delvin EE, Glorieux FH, Marie PJ, et al: Vitamin Ddependency: Replacement therapy with calcitriol. J Pediatr 99:2634,198l 3. Rosen JF, Fleischman AR, Finberg L, et al: Rickets with alopecia: An inborn error of vitamin D metabolism. J Pediatr 94~729-735, 1979 4. Labuda M, Morgan K, Glorieux FH: Mapping autosomal recessive vitamin D dependency type I to chromosome 12q by linkage analysis. Am J Hum Genet (in press) 5. Winkler I, Schreiner F, Harmeyer J: Absence of renal 25 hydroxycholecalciferol-1-hydroxylase activity in a pig strain with vitamin D-dependent rickets. Calcif Tissue Int 38:87-94, 1986 6. Fraser D, Kooh SW, Kind PH, et al: Pathogenesis of hereditary vitamin D dependent rickets. N Engl J Med 89:717-722, 1973 7. Goodyear PR, Kronick JB, Jequier S, et al: Nephrocalcinosis and its relationship to treatment of hereditary rickets. J Pediatr 3:700-704, 1987 8. Tau C, Chabot G, Glorieux FH: Evaluation of renal function and pyramidal echogenicity in vitamin D resistant and dependent patients on long-term treatment. J Bone Min Res 4:S360, 1989 (suppl, abstr) 9. Glorieux FH, Striver CR: Loss of a PTH sensitive component of phosphate transport in X-linked hypophosphatemia. Science 175:977-1000,1972 10. Read AP, Thakker RV, Davies KE, et al: Mapping of human X-linked hypophosphataemic rickets by multilocus linkage analysis. Hum Genet 73:267-270, 1986 11. Walton RJ, Bijvoet OLM: A simple slide-rule method for the assessment of renal tubular reabsorption of phosphate in man. Clin Chim Acta 81:273-276, 1977 12. Delvin EE, Glorieux FH: Serum 1,25-dihydroxivitamin D concentration in hypophosphatemic vitamin D-resistant rickets. CalcifTissueInt 33:173-175, 1981 13. Lyles KW, Drezner MK: Parathyroid hormone effects on serum 1,25_dihydroxyvitamin D levels in patients with X-linked hypophosphatemic rickets: Evidence for abnormal 25-hydroxyvitamin D-1-hydroxylase activity. J Clin Endocrinol Metab 54:638-644, 1982 14. Drezner MK: Understanding the pathogenesis of X-linked

hypophosphatemic rickets: A requisite for successful therapy, in Cases in Metabolic Bone Disease, vol 2. New York, NY, Triclinica Communications, 1987, pp 1- 11 15. Stern PH, Taylor AB, Bell NH, et al: Demonstration that circulating ln,25-Dihydroxyvitamin D is loosely regulated in normal children. J Clin Invest 68:1374-1377, 1981 16. Glorieux FH, Striver CR, Reade TM, et al: The use of phosphate and vitamin D to prevent dwarfism and rickets in X-linked hypophosphatemia. N Engl J Med 281:481,1972 17. Glorieux FH, Bordier PJ, Marie P, et al: Inadequate bone response to phosphate and vitamin D in familial hypophosphatemic rickets, in Massry S, Ritz E, Rapado A (eds): Homeostasis of Phosphate and Other Minerals. New York, NY, Plenum, 1978, pp 227-232 18. Glorieux FH, Marie PJ, Pettifor JM, et al: Bone response to phosphate salts, ergocalciferol and calcitriol in hypophosphatemic vitamin-Dresistant rickets. N Engl J Med 303:1023-1031,198O 19. Costa T, Marie PJ, Striver, et al: X-linked hypophosphatemia. Effect of calcitriol on renal handling of phosphate, serum phosphate, and bone mineralization. J Clin Endocrinol Metab 52:463-472,198l 20. Drezner MK, Lyles KW, Haussler MR, et al: Evaluation of a role for 1,25dihydroxyvitamin D in the pathogenesis and treatment of X-linked hypophosphatemic rickets and osteomalacia. J Clin Invest 66:1020-1032, 1980 21. Harrell RM, Lyles K, Harrelson JM, et al: Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol. J Clin Invest 75:1858-1868, 1985 22. Rasmussen H, Pechet M, Anast C, et al: Long-term treatment of familial hypophosphatemic rickets with oral phosphate and la-hydroxyvitamin D,. J Pediatr 99:16-25,198l 23. Frost HM: Some observations on bone mineral in a case of vitamin D resistant rickets. Henry Ford Hosp Med Bull 6:300-303, 1958 24. Glorieux FH, Ecarot-Charrier B: X-linked vitamin-D resistant rickets: Is osteoblast activity defective?, in Cohn DV, Martin TJ, Meunier PJ (eds): Calcium Regulation and Bone Metabolism, vol 9. Amsterdam, The Netherlands, Elsevier Science, 1987, pp 227-231

Calcitriol treatment in vitamin D-dependent and vitamin D-resistant rickets.

Use of 1,25(OH)2D3 (calcitriol) can be of benefit in the treatment of two hereditary types of rickets and osteomalacia, vitamin D dependency type I (V...
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